While estrogen therapy remains the most widely used agent for the prevention and treatment of osteoporosis, its potential side effects, including increasing breast cancer risk, mandate that other treatments be investigated. The anti-estrogens, particularly tamoxifen, are clearly effective in treatment and perhaps prevention of breast cancer, while also potentially possessing positive effects on the skeleton and serum lipoprotein profile. Therefore these agents might be useful for the prevention and treatment of osteoporosis as well as for general health maintenance in postmenopausal women. We have previously shown that estrogens decrease the sensitivity of the parathyroid gland to hyper- and hypocalcemia and decrease the sensitivity of the skeleton to the resorbing effects of PTH. We have also reported an estrogen-induced increase in biochemical markers of bone formation in response to 1,25(OH)2D administration and an increase in 1,25(OH)2D formation in response to exogenous or endogenous PTH. These studies have led to an increased understanding of the mechanism of estrogen action in the skeleton. There have been no similar dynamic studies investigating the mechanisms underlying the effects of anti-estrogens on the skeleton. In this application, we propose to evaluate the effects of tamoxifen and keoxifene, a more potent anti-estrogen, in comparison to estrogen and placebo on the PTH/Vitamin D/Mineral axis and skeletal turnover, by performing a series of dynamic investigations, including PTH and EDTA infusions, oral 1,25(OH)2D challenge, and intestinal calcium absorption testing, both before and after treatment with these agents in normal postmenopausal women. These studies will help provide the theoretical groundwork for use of anti-estrogens as preventative and therapeutic agents in osteoporosis.